1. Field of the Invention
The present invention relates to methods of ophthalmic administration. Specifically, the methods relate to intrascleral injection of therapeutic or diagnostic materials.
2. Description of the Related Art
Delivering therapeutic or diagnostic agents to the posterior segment of the eye, especially to the retina, macula, etc., poses several challenges. Topical instillation of an agent to the front of the eye such as by eye drops, generally provides low amounts of the agent (including none) to the posterior portion of the eye, due in part to poor diffusion through the various layers as well as the natural clearing processes encountered. Providing effective amounts of an agent to, for example, the retina via topical instillation is generally not possible given the distance and number of layers between the deposit site of the agent and the site to be treated. Another potential shortcoming with topical instillation is that the composition tends to be quickly removed from the eye by tears and other natural clearing processes. The resulting short duration of contact can further limit the likelihood of an appreciable amount of the agent reaching the posterior segment.
Conversely, systemic delivery of an agent to the posterior segment of the eye such as by oral administration, is limited by the blood-retinal barrier. The barrier limits the size and amount of agents that can reach the choroid and retina. Moreover, because the agent is systemically delivered, the dosage is limited so as not to provide a toxic dose of the agent to other parts of the body. This is especially a concern in treating chronic disorders where a long term dosing regimen is typically required. For this reason, overcoming the barrier by administering higher doses of the agent is usually not a practical alternative. Likewise, the risk of side effects is increased with systemic delivery.
Other proposals for delivering agents to the eye include the use of inserts and implants which release the agent over time onto or into the eye. An insert, as used in this application, is a device inserted over the eye, such as on the conjunctival layer, and generally comprises a polymer matrix containing an active agent. The agent that is released from the insert can diffuse through the sclera and into the eye. While sustained or long term agent contact with the eye can be achieved by this method, little if any of the agent reaches the posterior segment of the eye for much the same reasons as topical instillation. Implants are devices similar to inserts but they are surgically placed within the eye. Accordingly, implants bring the risk of infection and other problems due to its more invasive nature.
For example, U.S. Pat. No. 4,863,457 to Lee relates to an implant having a stem and base wherein the stem releases a drug and is positioned to extend into a canal, passageway, or orifice of the eye. The implant is taught to serve two functions: internal delivery of drug and mechanical prevention of passageway closure. The drawings illustrate placing the base of the implant in the subconjunctival space, or within the sclera itself, with the stem extending into the anterior chamber. The implant is taught to be especially useful in post-operative glaucoma patients as the drugs released can suppress scar tissue around the stem while the stem structure helps to maintain a passageway from the anterior chamber to Schlemm""s canal. In this way, the implant is taught to ensure continued drainage of the aqueous humor from the anterior chamber and prevent a recurrence of the pressure buildup caused by glaucoma.
However, this implant is directed to treating the anterior chamber and not the posterior segment of the eye. Indeed, the option of inserting the implant into the sclera is problematic if attempted in the posterior segment of the eye. Here, partially cutting the sclera where it overlies the retina and inserting the base and stem of the implant therein, raises the risk of retinal detachment and choroidal hemorrhage. Only in the front of the eye, where the sclera does not overlie the retina and the vasculature of the choroid is low, can the partial thickness sclera flap technique be practically performed. Accordingly, the design and placement of this implant is not effective for delivering an agent to the posterior portion of the eye.
U.S. Pat. No. 5,707,643 to Ogura et al. relates to a biodegradable scleral plug that is inserted through an incision in the sclera into the vitreous body. The plug releases a drug into the vitreous body for treating the retina. The path of the plug is not, however, indicated. Assumedly, the plug would extend through the avascular region of the pars plana so as not to rupture any significant blood vessels or the retina. The drug will be applied to the entire retina by diffusion through the vitreous body, thus precluding the ability to provide a more concentrated application of the drug to one portion of the retina. Also, the invasive nature of the plug brings various risks including the risk of infection.
U.S. Pat. No. 5,443,505 to Wong et al. relates to implants that are taught to deliver drug to a localized site. The implants are typically placed in the suprachoroidal space over an avascular region of the eye such as the pars plana or a surgically induced avascular region. Another embodiment involves forming a partial thickness scleral flap over an avascular region, inserting the implant onto the remaining scleral bed, optionally with holes therein, and suturing closed the flap. The drug diffuses into the vitreous region and the intraocular structure. Locating the implant close to the back of the eye is apparently not possible as the region would not be avascular, unless surgery is performed to make an avascular region. Such removal is normally undesirable since vision loss will be induced.
Another delivery approach is direct injection. For the posterior segment of the eye, an intravitreal injection has been used to deliver drugs into the vitreous body. U.S. Pat. No. 5,632,984 to Wong et al. relates to the treatment of macular degeneration with various drugs by intraocular injection. The drugs are preferably injected as microcapsules. The intraocular injection into the posterior segment is taught to allow diffusion of the drug throughout the vitreous, the entire retina, the choroid and the opposing sclera. Similarly, U.S. Pat. No. 5,770,589 to Billson et al. relates to treating macular degeneration by intravitreally injecting an anti-inflammatory into the vitreous humor. These invasive injections are normally administered through the pars plana in order to minimize the damage to the eye. While drug is delivered to the posterior segment, it is not specifically administered to a target area such as the macula, but rather is supplied to the entire posterior segment. Additionally, the procedure has a high risk of infection and retinal detachment and has restricted use.
U.S. Pat. No. 5,767,079 to Glaser et al. relates to the treatment of ophthalmic disorders including macular holes and macular degeneration, by administration of TGF-xcex2. The method of administration varies depending upon the nature and location of the pathology. The patent contemplates placing an effective amount of the growth factor on the ophthalmic abnormality. In treating the macula and retina, the examples teach that a surgical procedure involving a core vitrectomy or a complete pars plana vitrectomy is performed before the growth factor can be directly applied. The patent does mention the possible use of, inter alia, an intrascleral injection. However, no specifics are given about such a procedure, nor is such a procedure well known in the art. Presumably, the patentee intended either administration to the sclera on the anterior segment of the eye at an avascular region or administration to the sclera behind the retina via a surgical procedure through the vitreous body, retina, and choroid. The former method will not provide a large amount of drug to the posterior segment, as discussed above with regard to topical instillation and implants. The latter method is a dramatic, highly invasive, technique that would be suitable only where partial vision loss has already occurred or was imminently threatened. Such a procedure carries a high risk of infection or retinal detachment as well as loss of vision and clearly is problematic for chronic administration.
U.S. Pat. No. 5,273,530 to del Cerro et al. relates to the intraretinal delivery and withdrawal of samples and a device therefor. Unlike direct intraocular injection techniques, the method disclosed in this patent avoids the use of a pars plana incision and instead uses an insertion path around the exterior of the orbit. The device, having a curved handle and a tip with collar, allows a cannula to be inserted through the posterior sclera and down into the subretinal space without passing through the vitreous body. The collar is stated to regulate the penetration to the desired depth. The method is basically directed to supplying cells to and/or withdrawing samples from the subretinal space. However, the device is taught to be adjustable to any part of the eye including the scleral area, the choroidal area, the subretinal area, the retinal area and the vitreous area. In use, the disclosed subretinal delivery method presents a significant risk of causing choroidal hemorrhaging. It should be noted that although the approximate location of the cannula can be observed through a slit lamp by tinting, the penetration of the cannula through the sclera and choroid can not be seen until the tip of the cannula penetrates the retinal surface.
The above methods show that delivering agents to the posterior segment of the eye, especially the back of the eye at the retina, macula, etc., is difficult. This region of the eye is isolated by both the anterior segment and the blood-retinal barrier. The techniques which are relatively easy to apply (topical instillation, oral administration) generally do not deliver a sufficient amount of the agent to the posterior segment and/or present toxicity or side effect problems. In contrast, techniques that deliver effective amounts (intravitreal injection) are complicated, invasive procedures that subject the patient to the risk of infection, retinal detachment, and further vision or eye damage. A minimally invasive method for delivering agents to the posterior segment of the eye would be of great benefit.
It is an object of the present invention to provide a method for administering agents to the eye.
It is another object of the present invention to provide a method for administering agents to the eye that is minimally invasive.
Preferred forms of the invention contemplated accomplish at least one of the above objects. One embodiment of the invention is a method of intrascleral injection, which comprises injecting into the scleral layer of an eye through a location on the exterior surface of the sclera which overlies retinal tissue an effective amount of a therapeutic or diagnostic material. Depending on the injection conditions, the material will (1) form a depot within the scleral layer and diffuse into the underlying tissue layers such as the choroid and/or retina, (2) be propelled through the scleral layer and into the underlying layers, or (3) a combination of both (1) and (2). By entering the sclera from the external side, the method avoids the invasiveness of the intravitreal injection technique, thereby reducing the risk of infection and allowing a regimen of treatments to be given throughout the year, if needed. Also, because the sclera moves with the entire eye including the retina, the site of deposit on the sclera will map to the corresponding point on the underlying retina, even as the eye moves within the eye socket. This means that site specific delivery can be achieved and maintained. Thus, by depositing material into the sclera at a site overlying the macula, the material will be easily delivered to the macula and surrounding tissues.
The injection procedure is not particularly limited and embraces the use of a cannula or needle as well as needle-less particle/solution techniques. In a preferred embodiment, a cannula is inserted into the sclera in a rotational direction relative to the eye and not orthogonal to the surface of the sclera. By angling the cannula insertion into the sclera, the risk of accidentally perforating the sclera and causing damage to the underlying tissue (choroid and/retina) or hemorrhaging can be reduced or eliminated.
The present invention allows the delivery of a variety of agents to the posterior segment of the eye whenever such delivery would be desirable, including treating conditions of the posterior or anterior segments and diagnosing various conditions.